The profile of serum tumor-associated proteins is useful as a biomarker in detecting cancer at early stages, monitoring disease progression, and determining therapeutic response. Drug-responsive biomarkers are particularly critical for the selection of patients in whom the drug efficacy is expected. Currently, there are no serum biomarkers available for evaluation of the early tumor cell response during DR5-mediated apoptosis.
In many cases of anticancer therapies, biomarkers are critical to predict efficacy of the therapy for individual subjects. Biomarkers can be used to predict efficacy before treatment or can be monitored to predict the therapeutic response shortly after initiation of treatment. These biomarkers are useful to select appropriate subjects for the therapy and to save remaining subjects, in whom the therapy is unlikely to exhibit any clinical benefit, from unnecessary side effects and costs. Therefore, it becomes requisite to discover predictive biomarkers for anticancer drug development. Nevertheless, there are only a few biomarkers available for determining treatment, although many effective cancer therapies have been developed. For example, expression of estrogen receptor and/or progesterone receptors in breast cancers can predict therapeutic response to tamoxifen. Breast cancers with overexpression of the HER2/neu (ErbB2) proto-oncogene are more likely to respond to a humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin).
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also called Apo2L, is a member of the TNF superfamily and has an ability to trigger apoptosis in a variety of transformed cell lines. Five receptors for TRAIL have been identified: two death receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2), that transduce the apoptosis signal, and three decoy receptors, DcR1(TRAIL-R3), DcR2 (TRAIL-R4), and osteoprotegrin, that inhibit TRAIL-induced apoptosis. DR4 and DR5 contain a cytoplasmic death domain that is essential for induction of apoptosis. After binding of TRAIL to DR4 and/or DR5, these receptors initiate apoptosis through recruitment of the adaptor Fas-associated death domain and the initiator caspase-8 to form the death-inducing signaling complex, which leads to activation of the effector caspase cascade and eventual cell death.
TRAIL induces apoptosis only in tumorigenic or transformed cells, but not in normal cells, although TRAIL mRNA is expressed constitutively in many human normal tissues. It is suggested that there may be some mechanisms that protect normal cells from apoptosis induced by TRAIL. Preclinical studies in mice and nonhuman primates have shown that recombinant soluble TRAIL has an antitumor efficacy in various human tumor xenograft models and no significant toxicity to normal tissues. However, it has also been reported that some forms of recombinant soluble TRAIL induce apoptosis in normal human hepatocytes in vitro, suggesting potential liver toxicity in humans, although it may be caused by the form of recombinant soluble TRAIL. The anti-human DR5 monoclonal antibody TRA-8 and humanized versions of TRA-8 induce apoptosis in cancer cells both in vitro and in vivo, without hepatocellular toxicity. However, various degrees of sensitivity have been observed among cancer cells.